On average, patients' levels of urinary-free cortisol fell by about 50% during a six-month, phase III trial, Beverly Biller, MD, of Massachusetts General Hospital in Boston, and colleagues reported at the Endocrine Society meeting.

"Pasireotide may provide an option for pituitary-directed medical therapy targeting the underlying cause of the disease," Biller said.

Currently, there are no medical therapies specifically indicated for Cushing's disease. Surgery is the main therapeutic option, followed by radiation, and a handful of medications are used off-label.

The investigational agent pasireotide has a high affinity for the sst5 receptor, which is commonly expressed in corticotroph adenomas, a major cause of Cushing's disease.

It was previously shown to be effective in a 15-day phase II study, Biller said.

So to follow up, the researchers conducted a blinded, phase III trial, enrolling 162 patients with the disease at centers in 18 countries. Most had been refractory to prior treatments, including surgery, but some de novo patients were included if they weren't candidates for pituitary surgery.

The cohort was randomized to two injections of either 600 µg or 900 µg of pasireotide per day.

After three months, nonresponders were unblinded and their dose was upped by 300 µg, while all others continued on the same double-blind dose through six months. Doses were then titrated in all patients, as needed through one year.

The vast majority of patients (77%) were female.

The researchers found that urinary-free cortisol levels fell quickly, within the first one to two months after treatment, and significantly for patients on both doses of the drug.

The median decrease in cortisol from baseline to two months was about 50% in both groups and remained stable through the end of the study.

At six months, 14.6% of those on the 600-µg dose and 26.3% of those on the 900-µg dose met the primary endpoint of having urinary-free cortisol levels at or below the upper limit of normal. Those percentages were similar after a year at 13.4% and 25%, respectively.

In subgroup analyses, Biller and colleagues found that patients with lower baseline levels of cortisol had greater normalization of the hormone.

Although the compound generally had a safety profile similar to that of other somatostatin analogues -- largely gastrointestinal side effects -- 73% of patients had a hyperglycemic event. Biller said fasting plasma glucose and HbA1c levels rose in the patients soon after starting on the drug and returned to normal once the drug was stopped.

During her presentation, Biller said that among the 67 normoglycemic patients at baseline, 43% became pre-diabetic and 34% became diabetic during treatment.

This finding, she said, led to additional investigation into the drug's mechanism, which revealed that the drug reduces incretin and insulin secretion, without affecting insulin sensitivity. The addition of a GLP-1 agonist appeared to mitigate the effects, she said.

Some patients (8%) also experienced hypocortisolism, which was responsive to a dose reduction, the researchers said.

Though 75% of patients completed six months of the trial, just under half (48%) completed the full year. Most (25%) said they discontinued treatment because of an unsatisfactory therapeutic effect while 17.3% left because of adverse events.

Biller also noted that there were simultaneous reductions in blood pressure, weight, and LDL cholesterol, as well as reported improvements in quality of life.

The study was limited because it lacked a control group, but researchers at the meeting were largely pleased with the results.

"This is a good beginning," said George Chrousos, MD, of Athens University in Greece, who moderated the session at which the study was presented. "Other [off-label pharmacologic] options don't treat the actual cause like this does. They just alleviate the symptoms."

Chrousos said those other treatments are directed to the adrenal system while pasireotide targets tumors of the pituitary gland, the source of the problem.

"It's an advance but it's not the final step" in treating Cushing's disease with medical therapy, he said.